(a) Field of Invention
This invention relates to a method for preventing the secretion of excessive, i.e., absolute or relative, amounts of glucagon in humans suffering from hyperglucagonemia. Accordingly, the method of the invention is useful for relieving a complication arising from abnormally increased physiological availability of glucagon.
(B) Prior Art
Due to better diagnostic techniques, the state of abnormally increased levels or glucagon, i.e. hyperglucagonemia, in humans is being observed more often and its implications being better understood. For instance, hyperglucagonemia occurs in patients suffering from starvation, diabetes, severe infection or severe trauma, D. W. Wilmore et al., Lancet, 1, 73 (1974). In addition, hyperglucagonemia occurs in the surgical patients, severely burnt patients, elderly people and patients with alpha-cell carcinoma of the pancreatic islets, R. C. G. Russell et al., Br. Med. J., 1, 10 (1975); C. I. Orton, et al., Br. Med. J., 2, 170 (1975); J. Marco et al., paper no. 115 at the 37th Annual Meeting of the American Diabetic Association & Endocrine Meeting, Chicago, Illinois, June 5-7, 1977; and M. H. McGavran et al., N. Engl. J. Med., 274, 1408 (1966). Concerning the state of hyperglucagonemia, it is to be understood that this term not only refers to abnormally increased levels of glucagon as compared to normal levels, i.e. 100 pg or less per milliliter of serum (e.g. see Willmore et al., and Russell et al, cited above), but also includes the condition characterized by the presence of a physiologically inappropriate high level of glucagon.
It is now realized that hyperglucagonemia causes such undersirable effects as abnormalities in carbohydrate metabolism and excessive increases in protein catabolism and urinary urea excretion, see Russell et al., cited above. Therefore, a well tolerated agent capable of blocking glucagon release or availability in man would have clinical value in limiting the metabolic derangements of hypercatabolic states induced by hyperglucagonemia.
The active agent of this invention, 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid, or a therapeutically acceptable salt thereof, is disclosed in U.S. Pat. No. 3,821,383, issued June 28, 1974. This active agent, hereinafter sometimes designated as "alrestatin", previously has been reported to be useful in preventing or relieving diabetic complications such as cataracts, neuropathy, nephropathy and retinopathy (see U.S. Pat. No. 3,821,383). I have now found unexpectedly that alrestatin, either in its free acid form or in its therapeutically acceptable salt form, is an inhibitor of glucagon release.
This finding, coupled with the fact that alrestatin is a relatively safe drug, renders the method of this invention particularly useful and advantageous.